The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).
RESEARCH INDEX
The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.
Audio Commentary by Dr Katrina Pears
ME/CFS Research Published 27 September – 3 October 2022
There have been six new ME/CFS studies and sixteen studies on Long Covid.
We have highlighted two studies below:
Paper two (2) is on the recent online surveys which were used to identify the research priorities for ME/CFS. In the first survey, UK participants submitted research questions about ME/CFS which are important to them, in which 1565 participants responded. In the second survey, participants prioritised frequently submitted questions from the 1st survey, this was completed by 1752 participants.
The ten important research priorities which have been identified cover the topics:
1. Post-exertional malaise,
2. Use of existing drugs for other conditions,
3. Diagnosis,
4. Autoimmunity,
5. Sub-types,
6. Post-infective cause,
7. Neurological symptomology,
8. Genetics,
9. Severe ME/CFS,
10. Mitochondrial dysfunction and 10 (equal) Oxygenation dysfunction.
These research questions are set out in full within the paper, but the full list is also easy to read on the James Lind Alliance website.
This piece of research identifying the research priorities in ME/CFS is certainly welcome and will hopefully lead to more directed research and funding, notably this will also assist in the government’s working party on ME/CFS research.
Although these priorities have been identified, whether they are practical to research has not been established. The study does not itself list any limitations on how these priorities were identified, but does represent the ME/CFS population with the majority of participants being white, middle-aged women (with ME/CFS). This study used only UK based participants, and I do wonder if the priorities would differ at all worldwide and if this will have any influence on a global scale, seeing as only a small proportion of research we cover in the Weekly Roundup is conducted in the UK.
Our communications Manager, Russell Fleming, is one of the authors of this study, he had this to say:
“I had the great pleasure of working alongside a very talented group of people to help produce the Top 10 Research Priorities for ME/CFS, and I am delighted that the Department of Health and Social Care is using this report in their initiatives to prioritise improvements in this field. Congratulations to everyone who took part in this PSP – and especially to those of you who completed the surveys – your efforts were very much appreciated!”
Paper three (3) is a protocol for using MRI scans to investigate the theory that abnormal neurovascular coupling (NVC) is the cause of ME/CFS. NVC is a crucial process in the brain, and refers to the mechanism that links the transient neural activity to the subsequent change in cerebral blood flow. This involves the amino acid glutamate and Ca2+ ions.
To establish the NVC theory, the researchers have set out three aims in which MRI scans will be used. In detail, this will include looking at the hemodynamic response function (HRF) (the transfer function linking neural activity with functional MRI (fMRI) signal), respiration response function (RRF), linking to fatigue severity as well as modelling the neural activity with a functional task.
The study intends to be a good size and will address many confounding factors, with 288 participants, broken down into: 91 ME/CFS, 61 individuals with chronic fatigue, 91 healthy controls with sedentary lifestyles and 45 with fibromyalgia.
Currently, this paper only demonstrates the workflow to be used, providing a sound methodology for others to use and confirm the results (when available), so there is no data at this stage. The study did commence in January 2020 and will be completed in December 2024. The premise of this study looks good, the researchers have considered a lot of factors for their methodology with a rigorous study planned, furthermore, using sedentary controls is a definite strength. There is hope that a neuromarker for diagnosis could come out of this study, and I am looking forward to seeing future results published on this.
You may also be interested in reading paper four (4) which is a review on oxidative stress in ME/CFS and Long Covid and suggests this is a contributor to both conditions.
In the Long Covid reference section, you may be interested in paper two (2) which shows that immune reactions to severe Covid-19 may trigger brain problems. Dr Charles Shepherd has also provided a comment on this study.
ME/CFS Research References and Abstracts
Sorg AL, Becht S, Jank M, Armann J, von Both U, Hufnagel M, Lander F, Liese JG, Niehues T, Verjans E, Wetzke M, Stojanov S, Behrends U, Drosten C, Schroten H, von Kries R.
JAMA Netw Open. 2022 Sep 1;5(9):e2233454.
Key Points
Question: Is SARS-CoV-2 seropositivity associated with symptoms of myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) in children and adolescents?
Findings: This cross-sectional study of hospital-based SARS-CoV-2 seroprevalence surveys in Germany compared seropositive and seronegative children and adolescents and identified an excess of possible ME/CFS symptoms with serological evidence of preceding SARS-CoV-2 infection. This association almost disappeared with adjustment for confounders and restriction to children and adolescents unaware of preceding infection.
Meaning: These findings suggest that the risk of ME/CFS after SARS-CoV-2 infection in children and adolescents may be small and that recall bias may contribute to risk estimates.
Abstract
Importance: During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures.
Objective: To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents.
Design, Setting, and Participants: This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021.
Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years.
Exposures: Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays.
Main Outcomes and Measures: Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue.
Results: Among 634 participants (294 male [46.4%] and 340 female [53.6%]; median age, 11.5 [IQR, 8-14] years), 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2–seropositive (40.0%) and 158 of 534 SARS-CoV-2–seronegative (29.6%) children and adolescents.
After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35 (95% CI, 1.03-1.78) to 1.18 (95% CI, 0.90-1.53) and for substantial fatigue from 2.45 (95% CI, 1.24-4.84) to 2.08 (95% CI, 1.05-4.13).
Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS–related symptoms. The adjusted risk ratio was 1.08 (95% CI, 0.80-1.46) for reporting clustered ME/CFS symptoms and 1.43 (95% CI, 0.63-3.23) for fatigue.
Conclusions and Relevance: These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic.
Sarah Tyson, Kristina Stanley, Toto Anne Gronlund, Sian Leary, Mike Emmans Dean, Claire Dransfield, Helen Baxter, Rachel Elliot, Rachel Ephgrave, Monica Bolton, Annette Barclay, Gemma Hoyes, Ben Marsh, Russell Fleming, Joan Crawford, Ann West, Opal Webster-Phillips, Cristina Betts, Susan O’Shea, Vinod Patel & Sonya Chowdhury
Fatigue: Biomedicine, Health & Behavior
Abstract
Objective: To identify research priorities of people with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and those who support and care for them.
Method: Using the James Lind Alliance’s protocols, online surveys and workshops were held. The first survey asked participants from the U.K. to submit research questions about ME/CFS which were important to them. In the second, participants prioritised frequently submitted questions from the 1st survey. These were short listed and then workshop discussions were held to reach consensus on the top ten research priorities.
Results: 1565 participated in the 1st survey and 5300 research priorities were submitted. 1752 participated in the 2nd. In both surveys, the predominant demographic was white, middle-aged women with ME/CFS. 15–17% were family/carers of people with ME/CFS and 4–6% were health and social care workers. From the 1st survey, 59 summary questions were identified. These were prioritised and short listed to 18 questions. Of these, the top 10 covered 1. Post-exertional malaise, 2. Use of existing drugs for other conditions, 3. Diagnosis, 4. Autoimmunity, 5. Sub-types, 6. Post-infective cause, 7. Neurological symptomology, 8. Genetics, 9. Severe ME/CFS, 10. Mitochronical dysfunction and 10 (equal) Oxygenation dysfunction.
Conclusion: People with ME/CFS, their families and carers, and health care professionals worked together to identify, for the first time, the research priorities for ME/CFS. These focus on the biomedical causes of ME/CFS and how to diagnose, treat and manage it. Researchers and funding bodies should consider these in their plans for future research.
Shan ZY, Mohamed AZ, Andersen T, Rendall S, Kwiatek RA, Fante PD, Calhoun VD, Bhuta S, Lagopoulos J.
Front Neurol. 2022 Sep 16;13:954142.
Abstract
Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a debilitating illness affecting up to 24 million people worldwide but concerningly there is no known mechanism for ME/CFS and no objective test for diagnosis.
A series of our neuroimaging findings in ME/CFS, including functional MRI (fMRI) signal characteristics and structural changes in brain regions particularly sensitive to hypoxia, has informed the hypothesis that abnormal neurovascular coupling (NVC) may be the neurobiological origin of ME/CFS.
NVC is a critical process for normal brain function, in which glutamate from an active neuron stimulates Ca2+ influx in adjacent neurons and astrocytes. In turn, increased Ca2+ concentrations in both astrocytes and neurons trigger the synthesis of vascular dilator factors to increase local blood flow assuring activated neurons are supplied with their energy needs.
This study investigates NVC using multimodal MRIs:
(1) hemodynamic response function (HRF) that represents regional brain blood flow changes in response to neural activities and will be modeled from a cognitive task fMRI;
(2) respiration response function (RRF) represents autoregulation of regional blood flow due to carbon dioxide and will be modeled from breath-holding fMRI;
(3) neural activity associated glutamate changes will be modeled from a cognitive task functional magnetic resonance spectroscopy. We also aim to develop a neuromarker for ME/CFS diagnosis by integrating the multimodal MRIs with a deep machine learning framework.
Methods and analysis: This cross-sectional study will recruit 288 participants (91 ME/CFS, 61 individuals with chronic fatigue, 91 healthy controls with sedentary lifestyles, 45 fibromyalgia). The ME/CFS will be diagnosed by consensus diagnosis made by two clinicians using the Canadian Consensus Criteria 2003. Symptoms, vital signs, and activity measures will be collected alongside multimodal MRI.
The HRF, RRF, and glutamate changes will be compared among four groups using one-way analysis of covariance (ANCOVA). Equivalent non-parametric methods will be used for measures that do not exhibit a normal distribution. The activity measure, body mass index, sex, age, depression, and anxiety will be included as covariates for all statistical analyses with the false discovery rate used to correct for multiple comparisons.
The data will be randomly divided into a training (N = 188) and a validation (N = 100) group. Each MRI measure will be entered as input for a least absolute shrinkage and selection operator—regularized principal components regression to generate a brain pattern of distributed clusters that predict disease severity. The identified brain pattern will be integrated using multimodal deep Boltzmann machines as a neuromarker for predicting ME/CFS fatigue conditions. The receiver operating characteristic curve of the identified neuromarker will be determined using data from the validation group.
Ethics and study registry: This study was reviewed and approved by University of the Sunshine Coast University Ethics committee (A191288) and has been registered with The Australian New Zealand Clinical Trials Registry (ACTRN12622001095752).
Dissemination of results: The results will be disseminated through peer reviewed scientific manuscripts and conferences and to patients through social media and active engagement with ME/CFS associations.
Max Oliver Mackay Walker, Katherine H Hall, Katie Peppercorn, Warren Perry Tate
Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022.
Abstract
Long COVID is now well accepted as an ongoing post-viral syndrome resulting from infection of a single virus, the pandemic SARS-CoV-2. It mirrors the post-viral fatigue syndrome, Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, a global debilitating illness arising mainly from sporadic geographically-specific viral outbreaks, and from community endemic infections, but also from other stressors.
Core symptoms of both syndromes are post-exertional malaise (a worsening of symptoms following mental or physical activity), pervasive fatigue, cognitive dysfunction (brain fog), and sleep disturbance.
Long COVID patients frequently also suffer from shortness of breath, relating to the lung involvement of the SARS-CoV-2 virus. There is no universally accepted pathophysiology, or recognized biomarkers yet for Long COVID or indeed for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Clinical case definitions with very similar characteristics for each have been defined. Chronic inflammation, immune dysfunction, and disrupted energy production in the peripheral system has been confirmed in Long COVID and has been well documented in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Neuroinflammation occurs in the brain in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome as shown from a small number of positron emission tomography and magnetic resonance spectroscopy studies, and has now been demonstrated for Long COVID.
Oxidative stress, an increase in reactive oxygen and reactive nitrogen species, and free radicals, has long been suggested as a potential cause for many of the symptoms seen in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, resulting from both activation of the brain’s immune system and dysregulation of mitochondrial function throughout the body.
The brain as a high producer of energy may be particularly susceptible to oxidative stress. It has been shown in peripheral immune cells that the balanced production of proteins involved in regulation of the reactive oxygen species in mitochondria is disturbed in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome.
Fluctuations in the chronic low level neuroinflammation during the ongoing course of Long COVID as well as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome have been proposed to cause the characteristic severe relapses in patients.
This review explores oxidative stress as a likely significant contributor to the pathophysiology of Long COVID and Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, and the mechanisms by which oxidative stress could cause the symptoms seen in both syndromes. Treatments that could mitigate oxidative stress and thereby lessen the debilitating symptoms to improve the life of patients are discussed.
Zhang Y, Jin F, Wei X, Jin Q, Xie J, Pan Y and Shen W.
Front. Pharmacol. 13:958005
Abstract
Objectives: This meta-analysis aimed to assess the effectiveness and safety of Chinese herbal medicine (CHM) in treating chronic fatigue syndrome (CFS).
Methods: Nine electronic databases were searched from inception to May 2022. Two reviewers screened studies, extracted the data, and assessed the risk of bias independently. The meta-analysis was performed using the Stata 12.0 software.
Results: Eighty-four RCTs that explored the efficacy of 69 kinds of Chinese herbal formulas with various dosage forms (decoction, granule, oral liquid, pill, ointment, capsule, and herbal porridge), involving 6,944 participants were identified.
This meta-analysis showed that the application of CHM for CFS can decrease Fatigue Scale scores (WMD: –1.77; 95%CI: –1.96 to –1.57; p < 0.001), Fatigue Assessment Instrument scores (WMD: –15.75; 95%CI: –26.89 to –4.61; p < 0.01), Self-Rating Scale of mental state scores (WMD: –9.72; 95%CI:–12.26 to –7.18; p < 0.001), Self-Rating Anxiety Scale scores (WMD: –7.07; 95%CI: –9.96 to –4.19; p < 0.001), Self-Rating Depression Scale scores (WMD: –5.45; 95%CI: –6.82 to –4.08; p < 0.001), and clinical symptom scores (WMD: –5.37; 95%CI: –6.13 to –4.60; p < 0.001) and improve IGA (WMD: 0.30; 95%CI: 0.20–0.41; p < 0.001), IGG (WMD: 1.74; 95%CI: 0.87–2.62; p < 0.001), IGM (WMD: 0.21; 95%CI: 0.14–0.29; p < 0.001), and the effective rate (RR = 1.41; 95%CI: 1.33–1.49; p < 0.001).
However, natural killer cell levels did not change significantly. The included studies did not report any serious adverse events. In addition, the methodology quality of the included RCTs was generally not high.
Conclusion: Our study showed that CHM seems to be effective and safe in the treatment of CFS. However, given the poor quality of reports from these studies, the results should be interpreted cautiously. More international multi-centered, double-blinded, well-designed, randomized controlled trials are needed in future research.
Manysheva K, Sherman M, Zhukova N, Kopishinskaia S.
Psychiatr Danub. 2022 Sep;34(Suppl 8):189-190.
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe, debilitating chronic disease characterized by marked tiredness and fatigue, cognitive dysfunction, sleep disturbances, pain, and autonomic, immunological, and metabolic dysfunctions, in which all symptoms are usually exacerbated by physical and/or psychological stress.
Subjects and methods: We report a case of ME/CFS with severe myalgia and severe locomotor disorders in a 25-year-old female after Gam-COVID-Vac vaccine (Sputnik V) ten days before the manifestation of the symptoms.
Results: This is the first report of such a complication from the Gam-COVID-Vac vaccine.
Long-COVID Research References
Dr Katrina Pears,
Research Correspondent.
The ME Association.
